Hemoglobin binding of monocyclic aromatic amines: Molecular dosimetry and quantitative structure activity relationships for the N-oxidation

Aromatic amines are important intermediates in industrial manufacturing. N-oxidation to the N-hydroxyarylamines is a key step determining the genotoxic properties of aromatic amines. N-hydroxyarylamines can form adducts with DNA, with tissue proteins and with the blood proteins albumin and hemoglobin in a dose-dependent manner. The determination of hemoglobin adducts is a useful tool for biomonitoring exposed populations. We have established the hemoglobin binding index (HBI) [(mmol compound/mol Hb)/(mmol compound/kg body wt)] of several aromatic amines in female Wistar rats. Including the values obtained by other researchers in the same rat strain, the logarithm of hemoglobin binding (log HBI) was plotted against the following parameters: the sum of the Hammett constants ( Σσ = σ p + σ m), p K a, log P (octanol/water), the half wave oxidation potential ( E 1 2 ) and the electronic descriptors of the amines and their corresponding nitrenium ions obtained by semiempirical calculations (MNDO, AM1 and PM3), such as atomic charge densities, energies of the HOMO and LUMO and their coefficients, the C-N bond order, the dipole moments and the ‘reaction enthalpy’ [MNDOHF, AM1HF or PM3HF = H f(nitrenium) − H f( rmamine )]. The correlation coefficients were determined from the plots of all parameters against log HBI for all amines by means of linear regression analysis. The amines were classified into three groups: group 1, all para-substituted amines, group 2, all amines with halogens and group 3, all amines with alkyl groups. For the amines of group 1, log HBI correlates with Σσ, MNDOHF, E 1 2 , the p K a and the log P with r = 0.84, 0.71, 0.73, −0.69 and 0.50, respectively. For the amines of group 2, log HBI correlates with p K a, Σσ, MNDOHF, E 1 2 and log P with r = 0.81, −0.76, −0.55, −0.46 and −0.20, respectively. For the amines of group 3, log HBI correlates with with E 1 2 , PM3HF, Σσ, p K a and log P with r = 0.92, 0.89, 0.76, 0.19 and 0.12, respectively. The apparent Michaelis-Menten constants K m and V max of the N-acetyltransferase of liver cytosol were determined for several amines. K m and V max do not correlate with any of the electronic descriptors. Female Wistar rats were dosed with nitroarenes. Hemoglobin binding of nitroarenes correlates with the energy levels of the LUMO. This investigation determines for a large variety of aromatic amines the bioavailability of the N-hydroxyarylamine — the genotoxic metabolite — and the utility of electronic des